丹参酮ⅡA磺酸钠抑制低氧性肺动脉高压大鼠模型白细胞介素6的表达

Inhibition of sodium tanshinone Ⅱ A sulfonate on the expression of interleukin-6 in anoxia rat models with hypoxic pulmonary hypertension

目的研究丹参酮ⅡA磺酸钠对低氧性肺动脉高压大鼠模型白细胞介素6（IL-6）表达的影响。方法将SD大鼠（n=32）按随机数字表法分为常氧对照组（A组）、缺氧模型组（B组）、丹参酮ⅡA磺酸钠低剂量（10mg·kg^1·d^-1）干预组（C组），丹参酮ⅡA磺酸钠高剂量（30mg·kg^-1·d^-1）干预组（D组），每组8只。将A组置于常氧中饲养，而B组、C组和D组大鼠则置于常压低氧舱中，低氧舱内氧浓度控制在（10±1）％。C组和D组从缺氧第1天开始，分别每天腹腔注射10mg／kg、30mg／kg的丹参酮ⅡA磺酸钠，A组和B组腹腔注射相同容积的生理盐水。连续饲养21d后，右心测压法检测各组大鼠的右心室收缩压及平均动脉压；苏木精-伊红（HE）染色观察大鼠肺小动脉血管形态及炎性反应的组织学变化；ELISA法检测血清的IL-6含量；实时荧光定量PCR法检测肺组织中IL-6的基因表达。结果低氧明显诱导了大鼠平均动脉压及右心室收缩压的升高，而经过丹参酮ⅡA磺酸钠干预后，这种升高显著降低，A、B、C、D各组大鼠的平均动脉压分别为（12．922±0．442）mmHg（1mmHg=0．133kPa）、（26．737±2．222）mmHg、（19．948±1．681）mmHg及（18．547±1．090）mmHg，右心室收缩压分别为（24．677±1．725）mmHg、（63．675±5．283）mmHg、（49．250±3．816）mmHg及（41．839±3．993）mmHg。丹参酮ⅡA磺酸钠改善了低氧性肺动脉高压大鼠肺小动脉血管形态改变及炎性反应，与B组相比，C、D组的肺小动脉管壁和平滑肌层增厚减轻，管腔狭窄及血管周围仅见少量的淋巴细胞及中性粒细胞浸润，但与A组相比，炎性反应仍明显。低氧诱导后，B组IL-6含量较A组明显升高（P〈0．05），丹参酮ⅡA磺酸钠处理后，C、D两组的IL-6含量较A、B组均降低（均P〈0．05），且C组IL-6含量高于D组（P〈0．05）。低氧明显诱导了肺组织中IL-6 mRNA的表达，丹参酮ⅡA磺酸钠则明显抑制低氧大鼠肺组织中IL-6 mRNA的表达水平，但仍高于常氧对照组，即B组〉C组〉D组〉A组（均P〈0．05）。结论丹参酮ⅡA磺酸钠可以有效治疗低氧引起的慢性肺动脉高压，可能与其对IL-6的抑制作用有关。

Objective To investigate the impact of sodium tanshinone Ⅱ A sulfonate （STS） on interleukin-6 （IL-6） expression in rat models with hypoxic pulmonary hypertension （HPH）. Methods The SD rats （n=32） were randomized into normoxic control group （group A）, hypoxia model group （group B）, low dose （ 10 mg·kg^-1·d^-1 ） of STS intervention group （group C ） and high dose （ 30 mg·kg^-1·d^-1） of STS group （group D） （n=8 each）. The group A was fed in normoxic cabin, while the rats of group B, C and D were put into the atmospheric hypoxic cabin, with the oxygen concentration of atmospheric hypoxic cabin being （10±1）%. On one hand, 10 mg/kg and 30 mg/kg STS were intraperitoneally infused into group C and group D at 1 d after hypoxia respectively. On other hand, the same dose of saline was intraperitoneally infused into group A and group B. After successive feeding of 21 d, right ventricular systolic pressure （RVSP） and mean arterial pressure （mPAP） were detected in rats of each group by right cardiac manometric method, the vascular morphology and inflammatory response observed by hematoxylin- eosin （HE） staining, IL- 6 component in serum measured by ELISA, and the IL- 6 expression detected by real- time fluorescent quantitative PCR. Results The hypoxia significantly induced the increases of RVSP and mPAP. Nevertheless, the increasing levels of RVSP and mPAP were obviously decreased after intervention of STS. The mPAPs were （12.922±0.442） mm Hg（ 1 mm Hg=0.133 kPa）, （26.737±2.222） mm Hg, （ 19.948±1.681 ） mm Hg and（18.547±1.090） mm Hg in A, B, C, D groups, and RVSPs were（24.677±1.725） mm Hg, （63.675±5.283） mm Hg, （49.250±3.816） mm Hg and （41.839±3.993） mm Hg respectively. STS could improve the vascular morphology and inflammatory response in rats with HPH. Compared with group B, group C and group D had reduced thickening of small arterial wall and smooth muscle layer, narrowing lumen and less lymphocytes and neutrophil infiltration in peripheral vessels. However, the inflammatory response in group C and group D remained obvious as compared with that in group A. After hypoxia induction, the IL-6 component in group B was significantly elevated as compared with that in group A （P〈0.05）. While after intervention of STS, the IL-6 components in group C and group D were lowered as compared with those in group A and group B（all P〈0.05）, with IL-6 component in group C higher than that in group D（P〈0.05）. Hypoxia significantly induced the expression of IL-6 mRNA in lung tissues, while STS obviously inhibited the expression of IL-6 mRNA. However, the expression levels in these groups were still higher than that in normoxie control group, with group B〉 group C〉 group D〉 group A （all P〈0.05）. Conclusion STS is effective in treatment of chronicity HPH caused by hypoxia, which may be correlated with its inhibiting effects on IL-6.